METRONIDAZOLE

Main information

  • Trade name:
  • METRONIDAZOLE- metronidazole tablet, film coated
  • Composition:
  • METRONIDAZOLE 500 mg
  • Administration route:
  • ORAL
  • Prescription type:
  • PRESCRIPTION DRUG
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • METRONIDAZOLE- metronidazole tablet, film coated
    United States
  • Language:
  • English

Therapeutic information

  • Therapeutic indications:
  • Symptomatic Trichomoniasis. Metronidazole tablets are indicated for the treatment of T. vaginalis infection in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures). Asymptomatic Trichomoniasis. Metronidazole tablets are indicated in the treatment of asymptomatic T. vaginalis infection in females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate assessment of abnormal cytological smears, additional smears should be performed after eradication of the parasite. Treatment of Asymptomatic Sexual Partners.   T. vaginalis infection is a venereal disease. Therefore, asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent reinfection of the partner. The decision as to whether to treat an asymptomatic male partner who h
  • Product summary:
  • Metronidazole Tablets USP, 250 mg White colored, round shaped, film coated, biconvex tablets with 'U' debossed on one side and '226' debossed on other side. Bottles of 50:     NDC 29300-226-46 Bottles of 100:   NDC 29300-226-01 Bottles of 250:   NDC 29300-226-52 Bottles of 500:   NDC 29300-226-05 Bottles of 1000: NDC 29300-226-10 Metronidazole Tablets USP, 500 mg White colored, capsule shaped, film coated biconvex tablets with 'U' debossed on one side and '227' debossed on other side. Bottles of 50:     NDC 29300-227-46 Bottles of 100:   NDC 29300-227-01 Bottles of 500:   NDC 29300-227-05 Bottles of 1000: NDC 29300-227-10 Storage and Stability:   Store at 20 0 C to 25 0 C (68 0 to 77 0 F) [See USP Controlled Room Temperature].  Protect from light.

Status

  • Source:
  • DailyMed - NLM - National Library of Medicine
  • Authorization status:
  • Abbreviated New Drug Application
  • Authorization number:
  • 12634-172-00, 12634-172-01, 12634-172-48, 12634-172-50, 12634-172-71, 12634-172-78, 12634-172-79, 12634-172-80, 12634-172-81, 12634-172-84, 12634-172-94, 12634-172-99
  • Last update:
  • 25-05-2019

Summary of Product characteristics: dosage, interactions, side effects

METRONIDAZOLE- metronidazole tablet, film coated

Apotheca Inc.

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Metronidazole Tablets USP

To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole

tablets and other antibacterial drugs, metronidazole tablets should be used only to treat or prevent

infections that are proven or strongly suspected to be caused by bacteria.

WARNING

Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS).

Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions

described in the INDICATIONS AND USAGE section below.

DESCRIPTION

Metronidazole tablets, 250 mg or 500 mg is an oral formulation of the synthetic nitroimidazole

antimicrobial, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula:

Metronidazole tablets USP contain 250 mg or 500 mg of metronidazole. Inactive ingredients include

powdered cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hypromellose,

polyethylene glycol, stearic acid, and titanium dioxide.

CLINICAL PHARMACOLOGY

Abs orption

Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms.

Following oral administration, metronidazole is well absorbed, with peak plasma concentrations

occurring between one and two hours after administration.

Plasma concentrations of metronidazole are proportional to the administered dose. Oral administration

of 250 mg, 500 mg, or 2,000 mg produced peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40

mcg/mL, respectively. Studies reveal no significant bioavailability differences between males and

females; however, because of weight differences, the resulting plasma levels in males are generally

lower.

Dis tribution

Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also

being present. Less than 20% of the circulating metronidazole is bound to plasma proteins.

Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those

found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from

hepatic abscesses.

Metabolis m/Excretion

The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the

dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the

urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole

and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged

metronidazole accounting for approximately 20% of the total. Both the parent compound and the

hydroxyl metabolite possess in vitro antimicrobial activity.

Renal clearance of metronidazole is approximately 10 mL/min/1.73 m

. The average elimination half-

life of metronidazole in healthy subjects is eight hours.

Renal Impairment

Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole.

Subjects with end-stage renal disease (ESRD; CL

= 8.1±9.1 mL/min) and who received a single

intravenous infusion of metronidazole 500 mg had no significant change in metronidazole

pharmacokinetics but had 2-fold higher C

of hydroxy-metronidazole and 5-fold higher C

metronidazole acetate, compared to healthy subjects with normal renal function (CL

= 126±16

mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients,

monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS).

Effect of Dialysis

Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of

metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory

peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 to 8 hours removed 40% to 65% of

the administered metronidazole dose, depending on the type of dialyzer membrane used and the duration

of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis

session, supplementation of metronidazole dose following hemodialysis should be considered (see

DOSAGE AND ADMINISTRATION). A peritoneal dialysis session lasting for 7.5 hours removed

approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is

needed in ESRD patients undergoing CAPD.

Hepatic Impairment

Following a single intravenous infusion of 500 mg metronidazole, the mean AUC

of metronidazole

was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in

patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively,

compared to healthy control subjects. There were no significant changes in the AUC

of hydroxyl-

metronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is

recommended in patients with severe (Child-Pugh C) hepatic impairment (see DOSAGE AND

ADMINISTRATION). No dosage adjustment is needed for patients with mild to moderate hepatic

impairment. Patients with mild to moderate hepatic impairment should be monitored for metronidazole

associated adverse events (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Geriatric Patients

Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with no apparent

renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy-metronidazole (active

metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared

to young healthy controls <40 years old. In geriatric patients, monitoring for metronidazole associated

adverse events is recommended (see PRECAUTIONS).

Pediatric Patients

In one study, newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole.

The elimination half-life, measured during the first 3 days of life, was inversely related to gestational

age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination

age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination

half-lives ranged from 109 to 22.5 hours.

Microbiology

Mechanism of Action

Metronidazole exerts antibacterial effects in an anaerobic environment by the following possible

mechanism: Once metronidazole enters the organism, the drug is reduced by intracellular electron

transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is

created and maintained which promotes the drug's intracellular transport. Presumably, free radicals are

formed which, in turn, react with cellular components resulting in death of the bacteria.

Metronidazole is active against most obligate anaerobes, but does not possess any clinically relevant

activity against facultative anaerobes or obligate aerobes.

Activity In Vitro and In Vivo

Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro

and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive anaerobes

Clostridium species

Eubacterium species

Peptococcus species

Peptostreptococcus species

Gram-negative anaerobes

Bacteroides fragilis group ( B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus)

Fusobacterium species

Protozoal parasites

Entamoeba histolytica

Trichomonas vaginalis

The following in vitro data are available, but their clinical significance is unknown:

Metronidazole exhibits in vitro minimum inhibitory concentrations (MIC's) of ≤8 mcg/mL or less against

most (≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of

metronidazole in treating clinical infections due to these bacteria have not been established in adequate

and well-controlled clinical trials.

Gram-negative anaerobes

Bacteroides fragilis group ( B. caccae, B. uniformis)

Prevotella species ( P. bivia, P. buccae, P. disiens)

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro

susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as

periodic reports that describe the susceptibility profile of nosocomial and community-acquired

pathogens. These reports should aid the physician in selecting an antibacterial drug product for

treatment.

Anaerobic Techniques

Quantitative methods are used to determine minimum inhibitory concentrations provide reproducible

estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria

susceptibility to metronidazole can be determined by the reference broth or agar dilution method

The MIC values obtained should be interpreted according to the following criteria:

Susceptibility Test Interpretive Criteria for Metronidazole

MIC (mcg/mL)

Interpretation

≤ 8

Susceptible (S)

Intermediate (I)

≥ 32

Resistant (R)

For protozoal parasites: Standardized tests do not exist for use in clinical microbiology laboratories.

A report of "Susceptible" indicates that the antimicrobial is likely to inhibit growth of the pathogen if

the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth

of the pathogen. A report of "Intermediate" indicates that the result should be considered equivocal,

and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should

be repeated. This category implies possible clinical applicability in body sites where the drug is

physiologically concentrated or in situations where a high dosage of the drug product is

physiologically concentrated or in situations where a high dosage of the drug product can be used.

This category also provides a buffer zone that prevents small uncontrolled technical factors from

causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is

not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations

usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure

the accuracy and precision of supplies and reagents used in the assay, and the techniques of the

individuals performing the test.

Standard metronidazole powder should provide a value within the

MIC ranges noted in the following table:

Agar and Broth Acceptable Quality Control Ranges for Metronidazole

Acceptable Quality Control Ranges for Metronidazole

QC Strain

Minimum Inhibitory Concentration (mcg/mL)

Agar

Broth

Bacteroides fragilis ATCC 25285

0.25–1.0

0.25-

Bacteroides thetaiotaomicron ATCC 29741

0.5–2.0

0.5-

INDICATIONS AND USAGE

Symptomatic Trichomoniasis. Metronidazole tablets are indicated for the treatment of T. vaginalis

infection in females and males when the presence of the trichomonad has been confirmed by appropriate

laboratory procedures (wet smears and/or cultures).

Asymptomatic Trichomoniasis. Metronidazole tablets are indicated in the treatment of asymptomatic

T. vaginalis infection in females when the organism is associated with endocervicitis, cervicitis, or

cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate

assessment of abnormal cytological smears, additional smears should be performed after eradication of

the parasite.

Treatment of Asymptomatic Sexual Partners. T. vaginalis infection is a venereal disease. Therefore,

asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has

been found to be present, in order to prevent reinfection of the partner. The decision as to whether to

treat an asymptomatic male partner who has a negative culture or one for whom no culture has been

attempted is an individual one. In making this decision, it should be noted that there is evidence that a

woman may become reinfected if her sexual partner is not treated. Also, since there can be considerable

difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures

cannot be relied upon in this regard. In any event, the sexual partner should be treated with

metronidazole tablets in cases of reinfection.

Amebiasis. Metronidazole tablets are indicated in the treatment of acute intestinal amebiasis (amebic

dysentery) and amebic liver abscess.

In amebic liver abscess, metronidazole tablet therapy does not obviate the need for aspiration or

drainage of pus.

Anaerobic Bacterial Infections. Metronidazole tablets are indicated in the treatment of serious

infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be

performed in conjunction with metronidazole tablet therapy. In a mixed aerobic and anaerobic infection,

antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to

metronidazole tablets.

INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess,

caused by Bacteroides species including the B. fragilis group ( B. fragilis, B. distasonis, B. ovatus, B.

thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus species, and

Peptostreptococcus species.

SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species including the B. fragilis

group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium

species.

GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and

postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group,

Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species.

BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group and

Clostridium species.

BONE AND JOINT INFECTIONS, (as adjunctive therapy), caused by Bacteroides species including the

B. fragilis group.

CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused

by Bacteroides species including the B. fragilis group.

LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess,

caused by Bacteroides species including the B. fragilis group.

ENDOCARDITIS caused by Bacteroides species including the B. fragilis group.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole

tablets and other antibacterial drugs, metronidazole tablets should be used only to treat or prevent

infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and

susceptibility information are available, they should be considered in selecting or modifying

antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may

contribute to the empiric selection of therapy.

CONTRAINDICATIONS

Hypers ens itivity

Metronidazole tablets are contraindicated in patients with a prior history of hypersensitivity to

metronidazole or other nitroimidazole derivatives.

In patients with trichomoniasis, metronidazole tablets are contraindicated during the first trimester of

pregnancy (see PRECAUTIONS).

Psychotic Reaction with Disulfiram

Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using

disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within

the last two weeks (see PRECAUTIONS, Drug Interactions).

Interaction with Alcohol

Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal

cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products

containing propylene glycol during and for at least three days after therapy with metronidazole (see

PRECAUTIONS, Drug Interactions).

WARNINGS

Central and Peripheral Nervous System Effects

Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy

(including optic neuropathy) have been reported with metronidazole.

Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia,

dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy.

CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole.

CNS lesions seen on MRI have also been described as reversible.

Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or

paresthesia of an extremity.

Convulsive seizures have been reported in patients treated with metronidazole.

Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can

occur within hours of dose administration and generally resolve after metronidazole therapy is

discontinued.

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the

benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS).

PRECAUTIONS

General

Hepatic Impairment

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of

metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), a reduced

dose of metronidazole is recommended. For patients with mild to moderate hepatic impairment, no

dosage adjustment is needed but these patients should be monitored for metronidazole associated

adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Renal Impairment

Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine,

resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole

associated adverse events is recommended (see CLINICAL PHARMACOLOGY).

Fungal Superinfections

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy

with metronidazole and requires treatment with a candidacidal agent.

Use in Patients with Blood Dyscrasias

Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or

history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no

persistent hematologic abnormalities attributable to metronidazole have been observed in clinical

studies. Total and differential leukocyte counts are recommended before and after therapy.

Drug-Resistant Bacteria and Parasites

Prescribing metronidazole in the absence of a proven or strongly suspected bacterial or parasitic

infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk

of the development of drug-resistant bacteria and parasites.

Information for Patients

Interaction with Alcohol

Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking

metronidazole and for at least three days afterward because abdominal cramps, nausea, vomiting,

headaches, and flushing may occur (see CONTRAINDICATIONS and PRECAUTIONS, Drug

Interactions ).

Treatment of Bacterial and Parasitic Infections

Patients should be counseled that metronidazole should only be used to treat bacterial and parasitic

infections. Metronidazole does not treat viral infections (e.g., the common cold). When metronidazole is

prescribed to treat a bacterial infection, patients should be told that although it is common to feel better

early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not

completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and

(2) increase the likelihood that bacteria will develop resistance and will not be treatable by

metronidazole in the future.

Drug Interactions

Dis ulfiram

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and

disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within

the last two weeks (see CONTRAINDICATIONS).

Alcoholic Beverages

Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or

products containing propylene glycol are consumed during or following metronidazole therapy (see

CONTRAINDICATIONS).

Warfarin and other Oral Anticoagulants

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral

coumarin anticoagulants, resulting in a prolongation of prothrombin time. When metronidazole is

prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be

carefully monitored.

Lithium

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been

associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium

and serum creatinine levels should be obtained several days after beginning metronidazole to detect any

increase that may precede clinical symptoms of lithium intoxication.

Bus ulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an

increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly

with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are

available, and concomitant administration with busulfan is medically needed, frequent monitoring of

busulfan plasma concentration should be performed and the busulfan dose should be adjusted

accordingly.

Drugs that Inhibit CYP450 Enzymes

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as

cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.

Drugs that Induce CYP450 Enzymes

The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or

phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels;

impaired clearance of phenytoin has also been reported.

Drug/Laboratory Test Interactions

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as

aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate

dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of

the assays in which interference has been reported involve enzymatic coupling of the assay to

oxidation-reduction of nicotinamide adenine dinucleotide (NAD

↔ NADH). Interference is due to the

similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies

of metronidazole in rats and mice, but not hamsters.

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in

which the animals were dosed on an intermittent schedule (administration during every fourth week

only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m

(similar

to the maximum recommended daily dose, based on body surface area comparisons). Malignant

lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice.

Mammary and hepatic tumors were increased among female rats administered oral metronidazole

compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed

and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in

mammals in vivo have failed to demonstrate a potential for genetic damage.

Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at

doses up at 400 mg/kg/day (similar to the maximum recommended clinical dose, based on body surface

area comparisons) for 28 days. However, rats treated at the same dose for 6 weeks or longer were

infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked

decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats

after an eight week, drug-free recovery period.

Pregnancy:

Teratogenic Effects: Pregnancy Category B

There are no adequate and well controlled studies of metronidazole in pregnant women. There are

published data from case-control studies, cohort studies, and 2 meta-analyses that include more than

5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester

exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants

exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than

ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the

use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm

delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal

outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the

risk of infant cancer following metronidazole exposure during pregnancy did not show an increased

risk; however, the ability of these studies to detect such a signal was limited.

Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not

known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the

maximum recommended human dose based on body surface area comparisons. There was no evidence

of harm to the fetus due to metronidazole.

Nursing Mothers

Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant

serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for

tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to

discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the

mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of

metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or

formula.

Geriatric Use

In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended

(see CLINICAL PHARMACOLOGY, PRECAUTIONS). Decreased liver function in geriatric

patients can result in increased concentrations of metronidazole that may necessitate adjustment of

metronidazole dosage (see DOSAGE AND ADMINISTRATION).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established, except for the treatment of

amebiasis.

ADVERSE REACTIONS

The following reactions have been reported during treatment with metronidazole:

Central Nervous System: The most serious adverse reactions reported in patients treated with

metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral

neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent

peripheral neuropathy has been reported in some patients receiving prolonged administration of

metronidazole, patients should be specifically warned about these reactions and should be told to stop

the drug and report immediately to their physicians if any neurologic symptoms occur. In addition,

patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion,

dysarthria, irritability, depression, weakness, and insomnia (see WARNINGS).

Gastrointestinal: The most common adverse reactions reported have been referable to the

gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and

occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation.

Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have

occurred; these may be associated with a sudden overgrowth of Candida which may occur during

therapy.

Dermatologic: Erythematous rash and pruritus.

Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.

Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis,

flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened

urine have been reported by approximately one patient in 100,000. Although the pigment which is

probably responsible for this phenomenon has not been positively identified, it is almost certainly a

metabolite of metronidazole and seems to have no clinical significance.

Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting

joint pains sometimes resembling "serum sickness." Rare cases of pancreatitis, which generally abated

on withdrawal of the drug, have been reported.

Patients with Crohn's disease are known to have an increased incidence of gastrointestinal and certain

extraintestinal cancers. There have been some reports in the medical literature of breast and colon

cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended

periods of time. A cause and effect relationship has not been established. Crohn's disease is not an

approved indication for metronidazole tablets.

OVERDOSAGE

Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental

overdoses. Symptoms reported include nausea, vomiting, and ataxia.

Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors.

Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days

of doses of 6 to 10.4 g every other day.

Treatment of Overdosage: There is no specific antidote for metronidazole overdose; therefore,

management of the patient should consist of symptomatic and supportive therapy.

DOSAGE AND ADMINISTRATION

Trichomonias is :

In the Female:

One-day treatment − two grams of metronidazole tablets, given either as a single dose or in two divided

doses of one gram each, given in the same day.

Seven-day course of treatment − 250 mg three times daily for seven consecutive days. There is some

indication from controlled comparative studies that cure rates as determined by vaginal smears and signs

and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment

regimen.

The dosage regimen should be individualized. Single-dose treatment can assure compliance, especially

if administered under supervision, in those patients who cannot be relied on to continue the seven-day

regimen. A seven-day course of treatment may minimize reinfection by protecting the patient long

enough for the sexual contacts to obtain appropriate treatment. Further, some patients may tolerate one

treatment regimen better than the other.

Pregnant patients should not be treated during the first trimester (see CONTRAINDICATIONS). In

pregnant patients for whom alternative treatment has been inadequate, the one-day course of therapy

should not be used, as it results in higher serum levels which can reach the fetal circulation (see

PRECAUTIONS, Pregnancy).

When repeat courses of the drug are required, it is recommended that an interval of four to six weeks

elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate

laboratory measures. Total and differential leukocyte counts should be made before and after re-

treatment.

In the Male: Treatment should be individualized as it is for the female.

Amebias is

Adults:

For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for 5 to 10 days.

For amebic liver abscess: 500 mg or 750 mg orally three times daily for 5 to 10 days.

Pediatric patients: 35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days.

Anaerobic Bacterial Infections

In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered

initially.

The usual adult oral dosage is 7.5 mg/kg every six hours (approx. 500 mg for a 70-kg adult). A

maximum of 4 g should not be exceeded during a 24-hour period.

The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower

respiratory tract, and endocardium may require longer treatment.

Dosage Adjustments

Patients with Severe Hepatic Impairment

For patients with severe hepatic impairment (Child-Pugh C), the dose of metronidazole tablets should be

reduced by 50% (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

Patients Undergoing Hemodialysis:

Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic

circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the

duration of the dialysis session, and other factors. If the administration of metronidazole cannot be

separated from the hemodialysis session, supplementation of metronidazole dosage following the

hemodialysis session should be considered, depending on the patient's clinical situation (see

CLINICAL PHARMACOLOGY).

HOW SUPPLIED

Metronidazole Tablets USP, 250 mg

White colored, round shaped, film coated, biconvex tablets with 'U' debossed on one side and '226'

debossed on other side.

Bottles of 50: NDC 29300-226-46

Bottles of 100: NDC 29300-226-01

Bottles of 250: NDC 29300-226-52

Bottles of 500: NDC 29300-226-05

Bottles of 1000: NDC 29300-226-10

Metronidazole Tablets USP, 500 mg

White colored, capsule shaped, film coated biconvex tablets with 'U' debossed on one side and '227'

debossed on other side.

Bottles of 50: NDC 29300-227-46

Bottles of 100: NDC 29300-227-01

Bottles of 500: NDC 29300-227-05

Bottles of 1000: NDC 29300-227-10

Storage and Stability: Store at 20

C to 25

C (68

to 77

F) [See USP Controlled Room

Temperature]. Protect from light.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of

Anaerobic Bacteria; Approved Standard -Eighth Edition. CLSI document M11-A8. Clinical and

Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial

Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI

document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite

2500, Wayne, Pennsylvania 19087, USA, 2013.

Rx only

Manufactured by:

UNICHEM LABORATORIES LTD.

Ind. Area, Meerut Road, Ghaziabad-201 003, India.

Marketed by:

Rochelle Park, NJ 07662

R-01-09/2013

13004259

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL- 500mg 20 count

METRONIDAZOLE

metronidazole tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:126 34-172(NDC:29 30 0 -227)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

METRO NIDAZO LE (UNII: 140 QMO216 E) (METRONIDAZOLE - UNII:140 QMO216 E)

METRONIDAZOLE

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYDRO XYPRO PYL CELLULO SE (UNII: RFW2ET6 71P)

HYDRO XYPRO PYL CELLULO SE, LO W SUBSTITUTED (UNII: 216 5RE0 K14)

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

PO WDERED CELLULO SE (UNII: SMD1X3XO9 M)

STEARIC ACID (UNII: 4ELV7Z6 5AP)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

white

S core

no sco re

S hap e

OVAL (capsule shaped)

S iz e

18 mm

Flavor

Imprint Code

U;227

Contains

Apotheca Inc.

Packag ing

#

Item Code

Package Description

Marketing Start Date Marketing End Date

1

NDC:126 34-172-

10 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

2

NDC:126 34-172-0 1 10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

3

NDC:126 34-172-48

21 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n

Pro duc t

4

NDC:126 34-172-50

50 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

5

NDC:126 34-172-71

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

6

NDC:126 34-172-78

28 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

7

NDC:126 34-172-79

25 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

8

NDC:126 34-172-

20 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

9

NDC:126 34-172-8 1 21 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

10

NDC:126 34-172-8 4 14 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11

NDC:126 34-172-9 4 4 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

12

NDC:126 34-172-

9 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 3458

0 6 /0 1/20 14

Labeler -

Apotheca Inc. (051457844)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Apo theca Inc.

0 514578 44

relabel(126 34-172) , repack(126 34-172)

Revised: 12/2015